Melanoma is a malignant tumor of melanocytes that are predominately found in skin, but can also be found in the bowel and eye. Although melanoma is not the most common form of skin cancer, it causes the majority of skin cancer related deaths. Melanoma incidence and mortality rates in fair-skinned populations are increasing worldwide. Approximately 160,000 cases of malignant melanoma are diagnosed in the world each year. Current treatments include surgical removal of the tumor, adjuvant treatment, chemotherapy, immunotherapy and radiation therapy.
RAF protein kinases are key components of signal transduction pathways by which specific extracellular stimuli elicit precise cellular responses in mammalian cells. Activated cell surface receptors activate ras/rap proteins at the inner aspect of the plasma-membrane which in turn recruit and activate Raf proteins. Activated RAF proteins phosphorylate and activate the intracellular protein kinases MEK1 and MEK2. In turn, activated MEKs catalyze phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK). Several cytoplasmic and nuclear substrates of activated MAPK are known that directly or indirectly contribute to the cellular response to environmental change. Three distinct genes have been identified in mammals that encode Raf proteins: ARAF, BRAF and CRAF (also known as RAF-1).
Inhibitors of RAF kinases have been suggested for use in disruption of tumor cell growth and in the treatment of cancers, such as histiocytic lymphoma, adenocarcinoma, small cell lung cancer, melanoma and pancreatic and breast carcinoma. Specific inhibitors of BRAF mutants, such as V600E (BRAFV600E mutant) are known and have been used for the treatment of cancer. However, some subjects are refractory to treatment with BRAF inhibitors. Furthermore, some subjects develop secondary resistance to BRAF inhibitors, such that regression induced by a BRAF inhibitor is only temporary. Thus, a need remains for agents that augment the effect of BRAF inhibitors, such as a combination of agents of use for treating cancer and for inhibiting secondary resistance to a BRAF inhibitor.